medwireNews: The first positive trial findings for use of an oral Akt inhibitor, in combination with paclitaxel, in patients with locally advanced or metastatic triple-negative breast cancer have been published in The Lancet Oncology.

“Our results support future investigation of ipatasertib plus paclitaxel in diseases with high prevalence of PI3K/AKT pathway activation, particularly in patients with PIK3CA/AKT1/PTEN-altered tumours”, say lead LOTUS investigator Sung-Bae Kim, from the University of Ulsan College of Medicine in Seoul, South Korea, and team.

For the phase II trial, 124 women with treatment-naïve, inoperable disease were randomly assigned to receive paclitaxel 80 mg/m2 on days 1, 8 and 15 of each 28-day cycle alongside ipatasertib 400 mg/day or placebo on days 1–21.

The co-primary endpoint of superior median progression-free survival (PFS) with ipatasertib over placebo was met, at a median of 6.2 versus 4.9 months and a significant hazard ratio (HR) of 0.60.

But the co-primary endpoint of PFS in the subgroup of 48 patients with low expression of the tumour suppressor PTEN, as measured using immunohistochemistry, did not significantly between the ipatasertib (n=25) and placebo (n=23) arms, at 6.2 and 3.7 months, respectively.

Nevertheless, the investigators also report on the secondary endpoint of PFS for patients with and without PI3K/AKT pathway-activated tumours, defined as those with PTEN inactivating mutations or PIK3CA/AKT1 activating mutations.

Median PFS was significantly longer in the 26 patients with PIK3CA/AKT1/PTEN-altered tumours who were given ipatasertib than their 16 counterparts given placebo, at 9.0 versus 4.9 months and a HR of 0.44.

By contrast, in patients without PIK3CA/AKT1/PTEN tumour alterations, the corresponding median PFS values in the treatment arms were a comparable 5.3 and 3.7 months.

“This difference in efficacy based on absence of expression of PTEN through non-genetic mechanisms compared with loss of PTEN function through mutations and copy-number loss could be a key difference in how PTEN loss might drive tumours and be PI3K/AKT-addicted in prostate versus breast cancers”, hypothesize Sung-Bae Kim et al.

Suzette Delaloge and Louise DeForceville, from Gustave Roussy in Villejuif, France, agree in a linked comment that the LOTUS results should help “better define the targets and conditions of activity” of AKT inhibitors and other drugs targeting the PI3K pathway.

“If, as suggested by the results of LOTUS, genomic alterations are the preferred biomarker, testing of circulating tumour DNA might also be useful to allow better therapeutic targeting”, they suggest.

“Ongoing randomised studies testing precision medicine as a way to determine treatment rather than stratified approaches, such as SAFIR02 (NCT02299999), might also help us pick the best strategies and best drug combinations.”